Ageing (British English) or aging (American English) is the accumulation of changes in an organism or object over time. Aging in humans refers to a multidimensional process of physical, psychological and social change. Aging is defined as the gradual biological impairment of normal function, probably as a result of changes made to cells, molecules and tissues/morphological components. These changes have a direct impact on the functional ability of organs such as for example the heart, brain, kidney and lungs, biological systems such as for example the nervous, digestive and reproductive system and ultimately the organism as a whole.
Although aging affects the whole body the consequences of aging are related to the involved organ or system. The aging of arteries produces the most detrimental consequences of aging. Aging causes progressive decline in physiological arterial functions and morphology. Aging arteries generate changes in hemodynamic that importantly contribute to the development of cardiovascular diseases. In addition, aging arteries are more susceptible for the development of certain conditions such as atherosclerosis. Taken all facts together, arterial aging substantially contributes to the development and worsening of cardiovascular diseases such as for example myocardial infarction, stroke, dementia, critical limb ischemia, aortic aneurism, and similar. Thus, aging, specifically arterial aging, is one of most important risk factors for the development and worsening of cardiovascular diseases. It is widely believed that aging per se is not a modifiable risk factor. This conclusion does not necessarily apply to the arterial aging, however. Cardiovascular diseases remain the leading cause of morbidity and mortality in developed countries despite current intensive management strategies. Importantly, up to date, no effective treatment that would be able to prevent, reduce or even reverse the process of arterial aging has been disclosed.
Arterial aging is characterized by alterations in cells, matrix, and biomolecules present in the arterial wall. Arterial aging is a foundation for the initiation and progression of cardiovascular diseases. Although arterial aging literary starts immediately after birth, it seems that important age-related changes occur at middle age. In this period (approximately between 20-65 years) age-related changes gradually and continuously progress. Basic representative functional and morphological age-related arterial changes are for example endothelial dysfunction, vascular smooth muscle cell proliferation/invasion/secretion, matrix fragmentation, collagenisation and glycation that result in typical age related changes such as for example increased arterial stiffness and decreased arterial wall elasticity. Age-associated arterial wall phenotype creates a microenvironment enriched with reactive oxygen species and inflammatory molecules. Several age-modified angiotensin II signaling molecules control and facilitate the processes producing age-related arterial changes. Age-related arterial changes are clinically silent, but as described above may lead to development and worsening of cardiovascular diseases. Targeting arterial age/aging can reduce the incidence/occurrence and progression of said cardiovascular diseases.
Arterial aging is a result of gradual changes of morphological (i.e. structural) and functional properties of the arterial wall. The arterial wall consists of three layers: intima, media and adventia. The most inner part of the arterial wall is endothelium (a part of intima), which is directly exposed to the blood in the artery lumen. There is a large amount of evidence providing that aging itself induces the stiffening of media and consequently the stiffening of whole arterial wall (morphological property) and the impairment of endothelial function (functional property).
On the other hand, it is well known in the art that the functional and morphological properties of the arterial wall are also negatively influenced, if a subject has a cardiovascular disorder or a risk factor for a cardiovascular disorder. In fact, arterial aging may be accelerated, if a subject has a cardiovascular disorder or a risk factor for a cardiovascular disorder.
It is well known in the art that arterial stiffness and endothelial dysfunction are among the most important mechanisms facilitating the development and worsening of cardiovascular disorders such as hypertension, myocardial infarction, stroke, dementia, and similar. As regards the correlation between arterial aging, arterial stiffness, and cardiovascular risks, Mitchell at al. have found that increased arterial stiffness is a marker of increased cardiovascular risk, and arterial stiffness increases by aging. (Mitchell G F et al., Arterial stiffness and cardiovascular events: The Framingham Heart Study. Circulation 2010; 121:505-11). Thus, arterial aging, in particular affecting the gradual increase of arterial stiffness, increases the risk for cardiovascular disorders.
It is also well known in the art that one has to distinguish between arterial aging in apparently healthy subjects and arterial aging in connection with cardiovascular diseases (Najjar S. S. et al., Arterial Aging, Hypertension 2005; 46:454-462). When discussing apparently healthy subjects, Najjar et al. describe the changes in the arterial structure and function as part of “normative aging”, whereas when discussing cardiovascular diseases, they refer to accelerated changes which is not comparable to normative aging. Furthermore, J. M. Bowness reports that changes in the composition of the extracellular matrix associated with normal aging are clearly different from those occurring in the development of advanced atherosclerotic lesions (J. M. Bowness, Atherosclerosis and aging of the arterial wall, Can Med Assoc J 1992; 147(2):201). Moreover, H.-Y. Lee et al. disclose that arterial walls stiffen with age and that this aging process in the arterial tree is heterogeneous, with distal arteries not exhibiting these stiffening changes, which is different from the atherosclerotic process (H.-Y. Lee et al., Circulation Journal 2010; 94; 2258-2262).
Thus, arterial aging is different in unhealthy and healthy subjects, wherein unhealthy subjects are subjects e.g. having at least one cardiovascular disorder or having a risk factor for a cardiovascular disorder, and healthy subjects are subjects not having a cardiovascular disorder. Since arterial aging is typically correlated with a deterioration of the functional and morphological properties of the arterial wall, it can be concluded that also the properties of the arterial wall are affected depending on whether the subject is unhealthy (e.g. has a cardiovascular disorder) or healthy (e.g. does not have a cardiovascular disorder). On the other hand, both, arterial aging and deterioration of the properties of the arterial wall, facilitate the development and worsening of cardiovascular disorders.
The renin-angiotensin-aldosterone system (RAAS) plays an important role in regulating blood volume and systemic vascular resistance, which together influence cardiac output and arterial pressure. As the name implies, there are three important components to this system: renin, angiotensin, and aldosterone. Renin, which is primarily released by the kidneys, stimulates the formation of angiotensin in blood and tissues, which in turn stimulates the release of aldosterone from the adrenal cortex. When renin is released into the blood, it acts upon a circulating substrate, angiotensinogen, that undergoes proteolytic cleavage to form the decapeptide angiotensin I. Vascular endothelium, particularly in the lungs, has an enzyme, angiotensin converting enzyme (ACE), that cleaves off two amino acids to form the octapeptide, angiotensin II (AII), although many other tissues in the body (heart, brain, vascular) also can form AII.
Renin inhibitors are antihypertensive drugs that inhibit the first and rate-limiting step of RAAS. Since the 1970s scientists have been trying to develop potent inhibitors with acceptable oral bioavailability. The first and second generations faced problems like poor bioavailability and lack of potency. The third generation is non-peptidic renin inhibitors with acceptable oral bioavailability and potency for clinical use in the treatment of hypertension.
Angiotensin-converting enzyme (ACE) inhibitors produce vasodilation by inhibiting the formation of angiotensin II. This vasoconstrictor is formed by the proteolytic action of renin (released by the kidneys) acting on circulating angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme. ACE inhibitors also break down bradykinin (a vasodilator substance). Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors. ACE inhibitors are used primarily to treat hypertension, they may also be prescribed for cardiac failure, diabetic nephropathy, renal disease, systemic sclerosis, left ventricular hypertrophy and other disorders. ACE inhibitors are often used in conjunction with a diuretic in treating hypertension and heart failure.
Angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main use is in hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes), congestive heart failure, proteinuria, and prevention of cardiac remodeling after myocardial infarction. ARBs are receptor antagonists that block type 1 angiotensin II (AT1) receptors on bloods vessels and also in other tissues as arterial wall and heart muscle. ARBs act on the surface and inside arterial wall.
HMG-CoA reductase inhibitors also known as statins are a class of drug used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase that is the rate-controlling enzyme (EC 1.1.1.88) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMG-CoA reductase enzyme plays a central role in the production of cholesterol in the liver. Statins are among the most commonly prescribed drugs in medicine. Clinical studies have shown that statins significantly reduce the risk of heart attack and death in patients with proven coronary artery disease (CAD), and can also reduce cardiac events in patients with high cholesterol levels who are at increased risk for heart disease.
It is known that angiotensin II receptor antagonists and HMG-CoA reductase inhibitors posses the so called pleiotropic effects, this means effects beyond their primary action. Pleiotropic effects of a drug are actions other than those for which the agent was specifically developed. These effects may be related to or unrelated to the primary mechanism of action of the drug, and they are usually unexpected. As arterial-associated pleiotropic effects, both, angiotensin II receptor antagonists and HMG-CoA reductase inhibitors, could possibly improve endothelial function, they could act as antioxidants, they could have immunomodulatory effects, they could have anti-proliferative and anti-remodeling effects and similar beneficial vascular pleiotropic effects (Blum A et al. Atherosclerosis 2009; 203:325-30 and Jankowski P et al. Curr Pharm Des 2009; 15: 571-84).
Coronary heart disease (CHD) resulting from atherosclerosis is the single largest cause of death and approximately 40% of patients with hypertension have hypercholesterolemia, which is central to the pathogenesis of atherosclerosis and cardiovascular disease (CVD) (Kannel W B et al, Am J Hypertens 2000; 1:3; S-10S). Conversely, hypertension is a significant risk factor in patients with elevated cholesterol and there is a strong synergy between hypertension and hypercholesterolemia in terms of risk factors for the development of CVD (Sander G E, et al, Curr Hypertens Rep 2002; 4:458-463). Nickenig George, Circulation 2004, 110: 1013-1020 teaches on theoretical level that combination therapy of an ARB and an HMG-CoA reductase inhibitor would find utilization in people with cardiovascular risk factors and provocatively, also in people without symptomatic disease, but who are more than 55 years old, as age also becomes a risk factor for CVDs. Moreover, patients with two or more linked risk factors for CVD (such as for example type 2 diabetes mellitus, stroke, heart failure, metabolic syndrome and similar) would benefit from the combination of cholesterol lowering and antihypertensive drug therapy as well. The author concluded that further studies and combination in one pill would be appealing with respect to the efficient prevention of cardiovascular end points and would potentially increase treatment adherence in patients who have been prescribed long term poly-medication therapy.
Investigations carried by Zhen Li et al, Hypertension 2004; 44:758-763 suggested that concomitant AT1 receptor and cholesterol biosynthesis blockade blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects. They examined the possibility that statins may enhance the beneficial effects of an ARB on atherosclerosis. The study demonstrated that the combination of fluvastatin (well known representative of HMG-CoA reductase inhibitor) with valsartan (well known representative of ARB) has a preventive function regarding the development of atherosclerotic lesions. When ‘knockout’ mice that were fed with high caloric diet and that were consequently very susceptible to development of atherosclerosis received fluvastatin and valsartan at the beginning of parallel feeding, a decrease in observed atherosclerosis lesions size was found in comparison to the animals that did not receive the combination of fluvastatin and valsartan. These observations showed that the combination of fluvastatin and valsartan could prevent to the some degree development of atherosclerosis, but did not show that it might induce the reversal of already present atherosclerotic plaques. Therefore, the authors showed the possible protective effect of the combination but not the reversal effect of the same combination. From the clinical perspective it could be concluded that the authors showed only protective effects of the combination which could be applied only to subjects without any pathological changes whereas they did not show that the combination could induce the reversal of already present pathological changes.
Eiichiro Yamamoto et al, Arterioscler Thromb Vasc Biol 2007, 27:556-563 report that the combination of an ARB with an HMG-CoA reductase inhibitor may be the potential therapeutic strategy for vascular diseases of salt-sensitive hypertension. Their studies show that the combination of olmesartan (well known representative of ARB) and pravastatin (well known representative of HMG-CoA reductase inhibitor) exerts beneficial vascular effects in salt-sensitive hypertension, via differential pleiotropic effects and that pravastatin enhances vascular protective effects of olmesartan.
The report of Suzuki, Takayuki et al, Coronary Artery Disease: August 2011—Volume 22—Issue 5—p 352-358 discloses that the combination therapy of candesartan (well known representative of ARB) with an HMG-CoA reductase inhibitor inhibits progression of atherosclerosis more than HMG-CoA reductase inhibitor alone in patients with coronary artery disease.
From Yoshikawa M. et al, J Cardiovasc Pharmacol. 2009 February; 53(2):179-86 it is known that the combined treatment with an ARB and an HMG-CoA reductase inhibitor after stenting is useful for preventing stent restenosis.
G. B. John Mancini, et al, J Am Coll Cardiol, 2006; 47:2554-2560 report that the combination of ARBs and HMG-CoA reductase inhibitors reduced both cardiovascular (CV) and pulmonary outcomes. This combination was associated with a reduction in chronic obstructive pulmonary disease (COPD) hospitalization and total mortality not only in the high CV risk cohort but also in the low CV risk cohort. The combination also reduced myocardial infarction (MI) in the high CV risk cohort.
Atsuro Ichihara et al, Nephrol Dial Transplant (2002) 17: 1513-1517 in their study show on a relatively small number of patients (22 patients) in an observation period of 6 months that fluvastatin therapy (20 mg/day) reduces arterial stiffness, as measured by PWV (pulse-wave velocity), in haemodialysis patients with type 2 diabetes mellitus even if their serum lipid levels are within the normal ranges. The authors concluded that long-term administration of fluvastatin prevents further worsening of arterial biomechanics in haemodialysis patients with type 2 diabetes mellitus even in the presence of serum lipid levels in the normal range.
The first report on improvement in artery elasticity with an ARB was prepared by Janaka Karalliedde et al, Hypertension 2008, 51:1617-1623. The authors examined whether the ARB valsartan combined with hydrochlorothiazide (HCTZ) would improve arterial stiffness to a greater extent than an equivalent antihypertensive drug, the calcium channel blocker amlodipine in patients having type 2 diabetes mellitus with systolic hypertension and albuminuria. The 24-week single center, randomized, double-blind study (after a 4-week washout phase HCTZ 25 mg/daily was added to valsartan 160 mg—the maximum dose licensed for use in the UK) shows that the combination valsartan and hydrochlorothiazide improves arterial stiffness (measured by aortic PWV) and albumin excretion rate (marker of kidney disease) to a significantly greater extent than amlodipine.
A multi-centre, open label, controlled study performed by Ji Hyun Kim et al, (Diabetes Metab J. 2011 June; 35(3): 236-242) shows that 12 weeks treatment with angiotensin receptor blocker such as for example valsartan (an initial daily dose of 80 mg of valsartan was increased after 4 weeks to 160 mg/day for remaining 8 weeks) improves arterial stiffness (measured by pulse wave analysis) in patients with type 2 diabetes and hypertension, and that the glucose status at baseline is associated with this effect. The authors concluded that valsartan may be useful for delaying and reducing the influence of cardiovascular risk factors on arterial stiffness in high-risk patients such as those with both type 2 diabetes and hypertension.
Horiuchi et al, Circulation, 2003; 107: 106-112 demonstrates that a combination of low dose valsartan and low-dose fluvastatin acted synergistically to attenuate vascular neointimal formation at doses that were without effect when administered alone and were devoid of any effects on blood pressure or cholesterol levels.
Recent 3rd International Conference on Fixed Combination in the Treatment of Hypertension, Dyslipidemia and Diabetes Mellitus (November 2010) taught about several fixed combination products for the treatment of hypertension or hyperlipidemia, that have already been successfully placed on the market. None of the marketed combination product comprises RAAS inhibitor and HMG-CoA reductase inhibitor despite many literature providing beneficial effects of said combination. In addition, it was presented that of 1200 combinations reported in different studies only 45 were rated ‘effective’, what represents only 3.75%.
Therefore, the usefulness and effectiveness of combination of RAAS inhibitor and an HMG-CoA reductase inhibitor in the treatment of coronary and cardiovascular disorders has already been demonstrated in the studies of prior art. However, none of the studies teaches or describes or even gives any hint that a pharmaceutical composition comprising at least one RAAS inhibitor and at least one HMG-CoA reductase inhibitor, wherein the RAAS inhibitor and the HMG-CoA reductase inhibitor are each only present in a subtherapeutic daily dose, could be used for achieving a positive effect on functional and morphological properties of the arterial wall in a subject having at least one cardiovascular disorder or having at least one risk factor for cardiovascular disorder. Moreover, none of the studies describes or teaches or even gives any hint that a pharmaceutical composition comprising at least one RAAS inhibitor in a subtherapeutic daily dose and at least one HMG-CoA reductase inhibitor in a subtherapeutic daily dose could be used for the prevention, reduction and/or reversal of arterial aging and/or in decreasing the worsening or the occurrence of cardiovascular disorders in a subject having at least one cardiovascular disorder or having at least one risk factor for cardiovascular disorder. Moreover, the prior art literature does not relate to the dose dependent (dose-response) effect on arterial wall properties.
At the time being there is a general belief that the main strategy in treating or preventing cardiovascular disorders is to reduce the risk factors such as for example hypertension, hyperlipidemia, diabetes, smoking, but not to treat arterial wall directly in order to achieve the decrease of further impairment of arterial wall changes. Therefore, until now there is no treatment available which could reverse pathological arterial wall changes in subjects having at least one cardiovascular disorder or having at least one risk factor for cardiovascular disorder while there is a general belief that the above mentioned arterial wall changes are definitely irreversible and that the aim of treatment could be only the decrease of rate of further impairment. Therefore, novel approaches for maintaining or improving the functional and morphological properties of the arterial wall in subjects having at least one cardiovascular disorder or having at least one risk factor for a cardiovascular disorder are of great interest. Since the arterial wall properties are often also correlated with arterial age, there is also a need for a novel approach for preventing, reducing or reversing arterial aging in these subjects.
Apparently, novel approaches and strategies in treating cardiovascular disorders are of great interest. Therefore, the approach that is focused on the properties of arterial walls, particularly on functional and morphological properties and on arterial aging, that allows the preventing, reducing, or reversal of arterial changes would be a significant contribution to the art.
Furthermore, in view of the fact that active agents in pharmaceutical compositions may also cause negative side-effects, it is advantageous to use rather low doses of active agents in pharmaceutical compositions for the purpose of the invention.
In addition, due to long term persistence of beneficial arterial properties it is advantageous to use rest-period between two treatments for the purpose of the invention in order to prevent the occurrence of ‘resistance’. Moreover, there is no data in literature about possible prolonged effect in arterial functions after discontinuation of the treatment.
It is well-known that diabetes type I and type II induce accelerated and progressive impairment of functional and morphological properties of arterial wall and accelerate arterial aging. As the consequence, the occurrence or worsening of cardiovascular disorders in diabetic patients is facilitated leading to increased cardiovascular morbidity/mortality. The author of the present invention has clearly shown that a subtherapeutic daily dose combination of at least one renin-angiotensin-aldosterone system inhibitor and at least one HMG-CoA reductase inhibitor successfully improves (impaired) functional and morphological properties of the arterial wall, reduces or reverses the arterial aging and decreases the worsening or the occurrence of cardiovascular disorders in diabetic patients. It is important to emphasize that a subtherapeutic daily dose combination of at least one renin-angiotensin-aldosterone system inhibitor and at least one HMG-CoA reductase inhibitor treats the complication of diabetes (injured arterial wall), but not diabetes itself.